Introduction:. Despite 3 million adults in the United States being admitted annually for emergency general surgery (EGS) conditions, which disproportionately affect vulnerable populations, we lack an understanding of the barriers to round-the-clock EGS care. Our objective was to measure gaps in round-the-clock EGS care. Methods:. From August 2015 to December 2015, we surveyed all US-based adult acute care general hospitals that have an emergency room and ≥1 operating room and provided EGS care, utilizing paper and electronic methods. Surgeons or chief medical officers were queried regarding EGS practices. Results:. Of 2811 hospitals, 1634 (58.1%) responded; 279 (17.1%) were unable to always provide round-the-clock EGS care. Rural location, smaller bed size, and nonteaching status were associated with lack of round-the-clock care. Inconsistent surgeon coverage was the primary reason for lacking round-the-clock EGS care (n = 162; 58.1%). However, lack of a tiered system for booking emergency cases, no anesthesia availability overnight, and no stipend for EGS call were also associated with the inability to provide round-the-clock EGS care. Discussion:. We found significant gaps in access to EGS care, often attributable to workforce deficiencies.

Decellularized matrices of biologic tissue have performed well as wound care dressings. Extracellular matrix-based dressings are subject to rapid degradation by excessive protease activity at the wound environment. Stabilized, acellular, equine pericardial collagen matrix (sPCM) wound care dressing is flexible cross-linked proteolytic enzyme degradation resistant. sPCM was structurally characterized utilizing scanning electron and atomic force microscopy. In murine excisional wounds, sPCM was effective in mounting an acute inflammatory response. Postwound inflammation resolved rapidly, as indicated by elevated levels of IL-10, arginase-1, and VEGF, and lowering of IL-1β and TNF-α. sPCM induced antimicrobial proteins S100A9 and β-defensin-1 in keratinocytes. Adherence of Pseudomonas aeruginosa and Staphylococcus aureus on sPCM pre-exposed to host immune cells in vivo was inhibited. Excisional wounds dressed with sPCM showed complete closure at d 14, while control wounds remained open. sPCM accelerated wound re-epithelialization. sPCM not only accelerated wound closure but also improved the quality of healing by increased collagen deposition and maturation. Thus, sPCM is capable of presenting scaffold functionality during the course of wound healing. In addition to inducing endogenous antimicrobial defense systems, the dressing itself has properties that minimize biofilm formation. It mounts robust inflammation, a process that rapidly resolves, making way for wound healing to advance.-El Masry, M. S., Chaffee, S., Das Ghatak, P., Mathew-Steiner, S. S., Das, A., Higuita-Castro, N., Roy, S., Anani, R. A., Sen, C. K. Stabilized collagen matrix dressing improves wound macrophage function and epithelialization.

Collagenases are useful in enzymatic wound debridement. Clostridial collagenase, marketed as Collagenase Santyl Ointment (CSO), is FDA approved for such use. Building on the scientific premise that collagenases as well as collagen degradation products may regulate immune cell function, we sought to investigate the potential role of CSO in wound inflammation. We tested the hypothesis that in addition to enacting debridement, CSO contributes to the resolution of persistent wound inflammation. Wound macrophages were isolated from PVA sponges loaded with CSO or petrolatum and implanted in mice. Significant increase in pro-reparative and decrease in pro-inflammatory polarization was noted in macrophages of acute as well as diabetic wounds. Wound macrophages from CSO-treated group displayed increased production of anti-inflammatory cytokines IL-10 and TGF-β, and decreased levels of pro-inflammatory cytokines TNF-α and IL-1β. The active ingredient of CSO, CS-API, induced the expression of mϕheal /M(IL-4) polarization markers ex vivo. CS-API treatment attenuated transactivation of NF-κB and significantly induced STAT6 phosphorylation. A significant role of a novel PGE2-EP4 pathway in CS-API induced STAT6 activation and the mϕheal /M(IL-4) polarization was identified. Taken together, findings of this work reposition CSO as a potential agent that may be effective in resolving wound inflammation, including diabetic wounds.

Diabetic foot infection is one of the most common complications of diabetes mellitus and is a major cause of nontraumatic lower extremity amputation. Wound healing is a synchronized process aimed at restoration of tissue's structure and function. Diabetic wounds suffer from an impairment in cutaneous wound healing. Diabetic wounds are characterized by persistent infection and nonresolving inflammation that lead to chronicity of the wounds. Nutritional status of the patient dictates and governs the fate of the wound. Dietary supplementation using nutritional supplements to combat chronic inflammation in obese and diabetic patients is of growing interest. This chapter summarizes the concept and mechanisms of diabetic wound inflammation with an emphasis on nutraceutical interventions.

Reactive Oxygen Species (ROS) are small and highly reactive oxygen-containing molecules. ROS, when maintained at proper cellular concentrations, may function as “redox messengers” and play a significant role in intracellular signaling and regulation. On the other hand, when concentrations are higher than the physiological concentration, these radicals may be deleterious resulting in oxidative stress which may cause cell damage and cell death. This chapter elaborates the processes of ROS production, its physiological role, and the role of oxidative stress in cell death.

Persistent infection contributes to wound chronicity. At the wound site, NADPH oxidase (NOX) activity in immune cells fights infection to enable the healing process. Fermented papaya preparation (FPP) is a carbohydrate-rich nutritional supplement that has demonstrated ability to bolster respiratory burst in experimental rodent systems. In FPP, glucose coexists with fructose and maltose in addition to multiple other sugar alcohols such as inositol. We have previously reported that FPP supplementation augments wound healing in diabetic mice via improvement of respiratory burst activity of wound innate immune cells. In this clinical study ( clinicaltrials.gov : NCT02332993), chronic wound patients were orally supplemented with FPP daily. Inducible production of reactive oxygen species was significantly higher in wound-site immune cells from patients supplemented with FPP and on standard of care (SoC) for wound management compared with those patients receiving SoC alone. Wound closure in FPP-supplemented patients showed improvement. Importantly, the consumption of this mixture of carbohydrates, including significant amounts of glucose, did not increase HbA1c. These observations warrant a full-length clinical trial testing the hypothesis that FPP improves wound closure by augmenting NOX activity in immune cells at the wound site. Antioxid. Redox Signal. 28, 401-405.

Sustained high levels of activated polymorphonuclear leukocytes (PMNs) and PMN-derived proteases in the microenvironment of chronic venous leg ulcers (CVLUs) are linked to chronic inflammation and delayed healing. Uncontrolled PMN activity eventually destroys newly developed tissue and degrades critical growth factors. The bioactive components of fish oil (n-3 eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) have strong inflammation-resolving actions and have been shown to assuage PMN activity, but have not been tested in CVLU patients. This randomized controlled study compared the effectiveness of oral EPA + DHA therapy to a placebo for reducing PMN activation in CVLU microenvironments. At Days 0, 28, and 56, markers of PMNs (CD15) and activated PMNs (CD66b), and levels of PMN-derived proteases human neutrophil elastase and matrix metalloproteinase-8 were measured in CVLU fluid from patients receiving standard compression therapy and (1) EPA + DHA therapy (n = 16) or (2) placebo (n = 19). By Day 56, the EPA + DHA Group had a significantly lower percentage of CD66b+ cells in CVLU fluid compared to Day 0 (p = 0.02) and to Day 28 (p = 0.05). Importantly, there were downward trends in levels of both matrix metalloproteinase-8 and human neutrophil elastase over time in the EPA + DHA Group, which also demonstrated greater reductions in wound area by Day 28 (57% reduction) and Day 56 (76% reduction) than the Control Group (35% and 59%, respectively). Moreover, reductions in wound area had significant negative relationships with CD15+ cells in wound fluid at Days 28 (p = 0.008) and 56 (p < 0.001), and CD66b+ cells at Days 28 (p = 0.04) and 56 (p = 0.009). The collective findings provide supplemental evidence that high levels of activated PMNs in CVLU microenvironments inhibit healing, and suggest that EPA + DHA oral therapy may modulate PMN activity and facilitate healing of CVLUs when added to standard care regimens.

Chronic wounds affect a growing number of Americans, leading to reduced quality of life and causing a significant cost burden to the patient and to society as a whole. During a normal wound healing scenario, a wound will proceed through a well-organized progression of inflammation, proliferation, and remodeling to return form and function to an injury site. Proper nutrition status is required for this process to proceed to completion, whereas many wound patients suffering from malnutrition exhibit compromised healing outcomes. Often, chronic wounds result from unresolved inflammation, preventing the wound from continuing on the normal wound healing trajectory. In addition to meeting recommended macronutrient and micronutrient intake needs, there has been considerable work done in the area of functional foods and nutraceuticals as treatments to help reduce inflammation and promote wound healing. In this chapter, we describe the current spectrum of etiology and burden of chronic wounds as well as give an overview of the normal wound healing process, and where it often gets stalled in a proinflammatory phase. We aim to give a sampling of nutritional and nutraceutical interventions currently being studied that aim to address the issue of unresolved inflammation. By promoting the resolution of inflammation, it is thought that the normal wound healing progression may be restored, allowing for better wound outcomes.

Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a peripheral glycoprotein that acts as a bridging molecule between the macrophage and apoptotic cells, thus executing a pivotal role in the scavenging of apoptotic cells from affected tissue. We have previously reported that apoptotic cell clearance activity or efferocytosis is compromised in diabetic wound macrophages. In this work, we test the hypothesis that MFG-E8 helps resolve inflammation, supports angiogenesis, and accelerates wound closure. MFGE-8(-/-) mice displayed impaired efferocytosis associated with exaggerated inflammatory response, poor angiogenesis, and wound closure. Wound macrophage-derived MFG-E8 was recognized as a critical driver of wound angiogenesis. Transplantation of MFG-E8(-/-) bone marrow to MFG-E8(+/+) mice resulted in impaired wound closure and compromised wound vascularization. In contrast, MFG-E8(-/-) mice that received wild-type bone marrow showed improved wound closure and improved wound vascularization. Hyperglycemia and exposure to advanced glycated end products inactivated MFG-E8, recognizing a key mechanism that complicates diabetic wound healing. Diabetic db/db mice suffered from impaired efferocytosis accompanied with persistent inflammation and slow wound closure. Topical recombinant MFG-E8 induced resolution of wound inflammation, improvements in angiogenesis, and acceleration of closure, upholding the potential of MFG-E8-directed therapeutics in diabetic wound care.

Wound inflammation occurs in response to injury. It is a coordinated process involving tissues, cells, and an array of soluble, cell-associated, and intracellular factors. The role of certain microRNAs in wound healing and inflammation, in particular (a key process underpinning wound healing), has emerged in recent years. Here, mechanisms involving inflammatory cells, secreted molecules, and miRNAs that can affect wound healing are reviewed. Of interest miR-155, miR-146a, and miR-21, among others, have been shown to have a number of specialized roles in the inflammatory process, Toll-like receptor signaling, and efferocytosis. Other important miRNAs that regulate inflammation are also discussed.

Any tissue is made up of a heterogeneous mix of spatially distributed cell types. In response to any (patho) physiological cue, responses of each cell type in any given tissue may be unique and cannot be homogenized across cell-types and spatial co-ordinates. For example, in response to myocardial infarction, on one hand myocytes and fibroblasts of the heart tissue respond differently. On the other hand, myocytes in the infarct core respond differently compared to those in the peri-infarct zone. Therefore, isolation of pure targeted cells is an important and essential step for the molecular analysis of cells involved in the progression of disease. Laser capture microdissection (LCM) is powerful to obtain a pure targeted cell subgroup, or even a single cell, quickly and precisely under the microscope, successfully tackling the problem of tissue heterogeneity in molecular analysis. This review presents an overview of LCM technology, the principles, advantages and limitations and its down-stream applications in the fields of proteomics, genomics and transcriptomics. With powerful technologies and appropriate applications, this technique provides unprecedented insights into cell biology from cells grown in their natural tissue habitat as opposed to those cultured in artificial petri dish conditions.

Heterogeneity and high versatility are the characteristic features of the cells of monocyte-macrophage lineage.The mononuclear phagocyte system, derived from the bone marrow progenitor cells, is primarily composed of monocytes, macrophages, and dendritic cells.In regenerative tissues, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable.Macrophages are highly plastic cells.On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory type I macrophage (M1) or anti-inflammatory or proreparative type II macrophage (M2) phenotypes and transdifferentiate into other cell types.Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs.